There is growing enthusiasm in response to emerging data that combining immunotherapy with radiation therapy (RT) can increase response rates. However, persistent immunosuppression caused by radiation itself appears to limit this synergy. The effects of the exact RT delivery parameters (radiation modality, fractionation scheme, daily radiation exposure time and radiation dose rate) on the patient’s lymphocytes remain unknown, and there are currently no methods to calculate the radiation dose to circulating lymphocytes. The objective of this proposal is to develop a computational model to simulate the radiation dose to the lymphocyte population during intracranial irradiation based on vascular segmentation (SA1). The blood flow in the rest of the body will be modeled by a simplified Markov chain formalism. This will be combined with the patient-specific, time-dependent dose delivery information to simulate the dose to the circulating lymphocytes using a generalized Monte-Carlo approach. Furthermore we will validate our computational framework in patients treated with (conventional) photon and proton therapy. Due to the different dose distributions and time courses between proton and photon patients, we will be able to correlate the measured depletion in vivo to the patient-specific lymphocyte dose calculation to validate our computational model (SA2). Quantifying the dose delivered to the lymphocytes has great clinical potential and actionable significance because of the ease to modify radiation delivery parameters. Accurate knowledge of this effect would be transformative for the implementation of immunotherapy trials that are augmented with RT (>100 trials currently recruiting patients). Accurate dosimetry for circulating lymphocytes can control for variability among patients and will be key for the correct interpretation of trial results.